Central regulation of atherosclerosis by testosterone-deficiency

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Project Summary This proposal delineates a 4-year research career development program focused on brain mechanisms by which sex steroids protect from atherosclerosis. The candidate is currently a Research Assistant Professor in the Department of Medicine, Division of Metabolism, Endocrinology and Nutrition at University of Washington (UW). The proposed experiments and didactic work will provide the candidate with a unique set of multi- disciplinary skills for him to become an independent investigator in the cardiovascular field. The candidate has completed a PhD degree in Pharmacology at the University of Chile and two postdoctoral fellowships at OHSU and UW. The applicant’s combination of expertise in sex steroids biology and CNS regulation of metabolism uniquely qualify him to conduct these studies. In this proposal, he will address key questions in the field of cardiovascular disease, the answers to which will increase our understanding of the relationship between androgen deficiency and elevated cardiometabolic risk. Dr. Dorfman and his mentors (Drs. Karin E. Bornfeldt and Joshua P. Thaler) have created a specific training plan that takes advantage of the intellectual resources at the UW to guide him through the proposed educational activities and research. The goal of the current work is to work in mouse models to identify CNS mechanisms by which hypogonadism increases the incidence of cardiovascular events. Specifically, he will investigate the role of glial cells (microglia and astrocytes) in cardiometabolic changes that accelerate the progression of atherosclerosis. The proposal focuses on human evidence that low levels of circulating androgens promotes cardiometabolic dysregulation, and that hypothalamic gliosis is associated with lower endogenous testosterone and plasma LDL in men. Furthermore, the preliminary data identify a dramatic synergistic increase of hypothalamic gliosis when hypogonadism induced by castration and Western-type diet are combined; in this animal model, early markers of cardiometabolic risk are also evident including increased liver inflammation and triglyceride content, a shift toward very low density lipoprotein species, and circulating leukocytosis. These findings support studies proposed in Specific Aim 1 to use animal models with ablation of microglial or astrocyte inflammation to determine whether hypothalamic gliosis is required for Western-type diet and androgen deficiency to synergistically predispose to atherosclerosis. Additionally, the candidate has developed and validated a mouse model in which microglia and astrocytes can be pharmacologically activated through the use of Designer Receptors Exclusively Activated by Designer Drugs (DREADD) technology. These models of glial activation provide a tool to determine whether gliosis is sufficient to increase the risk of CVD as proposed in Aim 2.